Werner syndrome (WS) is a premature aging disorder with a complex phenotype, which includes many age-related disorders that develop from puberty, including greying and thinning of the hair, bilateral cataract formation, type II diabetes mellitus, osteoporosis and atherosclerosis. WS patients also experience an increased risk of rare non-epithelial cancers, especially sarcomas. Death usually occurs in the fourth decade from cardiovascular compromise or cancer. WS is caused by mutations of WRN gene, that play a major role in genome stability, particularly during DNA replication and telomere metabolism.
Category
Endocrine and metabolic disease
Brite
Human diseases in ICD-11 classification [BR:br08403]
20 Developmental anomalies
Multiple developmental anomalies or syndromes
LD2B Syndromes with premature ageing appearance as a major feature
H01733 Werner syndrome
Pathway-based classification of diseases [BR:br08402]
Replication and repair
nt06506 Double-strand break repair
H01733 Werner syndrome
RecQ helicases have crucial roles in the maintenance of genome stability. In humans, it is known that deficiencies in three of the five human RecQ helicases cause genetic disorders characterized by cancer predisposition, premature aging and developmental abnormalities. These disorders are Bloom's syndrome (BS), Werner's syndrome (WS), and Rothmund-Thomson syndrome (RTS), which are caused by mutations in BLM, WRN and RECQL4, respectively. Despite the apparent structural and biochemical similarities between the BLM, WRN and RECQL4 proteins, the phenotypes of BS, WS and RTS are different, suggesting that each disease pathway is functionally distinct to some extent. BS is characterized by most prominently, a predisposition to all types of cancers. WS is characterized by the premature development of features that resemble aging. RTS is characterized by skin and skeletal abnormalities, signs of premature aging, and cancer predisposition, especially to osteosarcomas. Recent research has shown many connections between all three proteins and the regulation of excess HR (Homologous recombination). It was also indicated that BLM is involved in repair of stalled DNA replication forks, and that WRN is required for telomere maintenance. Mutations in RECQL4 also associate with 2 additional syndromes, Rapadilino and Baller-Gerold syndrome.
Category
Congenital malformation
Brite
Human diseases in ICD-11 classification [BR:br08403]
04 Diseases of the immune system
Primary immunodeficiencies
4A01 Primary immunodeficiencies due to disorders of adaptive immunity
H00296 Defects in RecQ helicases
Pathway-based classification of diseases [BR:br08402]
Replication and repair
nt06506 Double-strand break repair
H00296 Defects in RecQ helicases
Van Maldergem L, Siitonen HA, Jalkh N, Chouery E, De Roy M, Delague V, Muenke M, Jabs EW, Cai J, Wang LL, Plon SE, Fourneau C, Kestila M, Gillerot Y, Megarbane A, Verloes A
Title
Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene.
